Functionalized chelants, or bifunctional coordinators, are known to be capable of being covalently attached to an antibody having specificity for cancer or tumor cell epitopes or antigens. Radionuclides complexes of such antibody/chelant conjugates are useful in diagnostic and/or therapeutic applications as a means of conveying the radionuclide to a cancer or tumor cell. See, for example, Meares et al., Anal. Biochem. 142, 68-78 (1984); and Krejcarek et al., Biochem. and Biophys. Res. Comm. 77, 581-585 (1977).
The present invention relates to a process for preparing isothiocyanto fuctionalized metal complexes. A radionuclide can be used in these complexes.
Isothiocyanto functionalized ligands are reported in the literature and are being used to conjugate radioactive isotopes to antibodies. For example see Gansow et al., Inorg. Chem. 25, 2772-81 (1986); Meares et al., Analytical Biochem. 142, 68-78 (1984); U.S. Pat. No. 4,454,106.
The methodology taught in the art to prepare such complexes involves treatment of an antibody/chelant conjugate with the radionuclide to form a complex followed by purification of the complex. A major disadvantage of such methodology is that the radionuclide (a lanthanide or transition metal) must be kinetically labile in order to be rapidly sequestered by the antibody/chelant conjugate.
Another disadvantage associated with the use of labile radionuclides for antibody labelling is that substitutionally labile trace metals (which are not radioactive) are frequently incorporated into the chelate. Competition for such non-active trace metals diminishes the biological efficacy of the antibody/chelate complex since a lower quantity of radionuclide is delivered to the target site.
Mikoler et al., European published application No. 139,675, teach the preparation of isothiocyanate fuctionalized chelates which can subsequently be conjugated to bio-organic molecules, e.g. haptens, antigens, antibodies. These complexes are prepared by chelating the isothiocyanate functionalized ligand.